We propose to use standard microelectrode techniques to study the electrophysiology and pharmacology of spontaneous impulse initiation in partially depolarized canine Purkinje fibers and myocardium. Abnormal automaticity will be induced in cardiac Purkinje cells and ventricular muscle by current clamp depolarization techniques, or by depolarization with BaCl2 or palmityl carnitine. Triggered activity from early after-depolarizations will be induced in isolated Purkinje fibers by treatment with N-acetyl procainamide. The response of both types of abnormal impulses will be studied by standard stimulation protocols (e.g., overdrive, premature stimulation, and intracellular current pulses), and will be compared with the results obtained from analogous studies on automaticity in normal fibers. We will study the effects of standard and experimental anti-arrhythmic drugs on these experimental models of abnormal automaticity, and on similar types of automatic activity that occur in pathological canine and feline cardiac fibers. In particular, we will study the effects of lidocaine, procainamide, propranolol, quarternary lidocaine derivatives, verapamil, AHR-2666, and a phenothiazine derivative (EN-313) on abnormal automaticity. These studies should give us insights into the electrophysiological mechanisms of cardiac arrhythmias, and may lead to improved pharmacotherapy. If time permits, we will extend a recently developed unipolar recording method to detect extracellular potentials from the endocardial surface of the in situ canine ventricle, to attempt to detect early afterdepolarizations and triggered activity in hearts made arrhythmic by (1) treatment with N-acetyl procainamide, or (2) delayed ectopic impulses occurring 24 hours after ligation of the left anterior descending coronary artery.